Prostate cancer is the most common malignancy in men, and, after lung cancer, the second leading cause of death in men. There were an estimated 217,730 new cases in 2010 resulting in 32,050 deaths. The majority of tumors are confined to the prostate. Others are clinically localized to the peri-prostatic area but extend through the prostatic capsule and may involve seminal vesicles. The remaining tumors are metastatic.
The absence of reliable diagnostic markers that enable early and accurate detection of tumors when they are confined to the prostate, as well as prognostic markers that enable prediction of disease progression, is a fundamental problem in the management of prostate cancer. Early detection and diagnosis of prostate cancer currently relies on digital rectal examination (DRE), prostate-specific antigen (PSA) measurement, transrectal ultrasonography (TRUS), and transrectal needle biopsy (TRNB). The leading diagnostic approach employs a combination of DRE and measurement of serum PSA; however, this approach has major limitations. Detection of an elevation in the level of PSA is more sensitive than specific (Thompson et al., NEJM 350: 2239-2246 (2004)). Consequently, more men are unnecessarily subjected to needle biopsy due to PSA screening and, unfortunately, the focal nature of prostate cancer results in needle biopsy sampling errors with false negative rates of 15-30% during diagnosis (Campos-Fernandes et al., Eur. Urol. 55: 600-609 (2009)). Out of the approximately 1.2 million patients who undergo prostate biopsy each year in the U.S., 70-80% receive negative results but cannot be reassured because a cancer might have been missed by sampling error (Norm et al., Prostate 69: 1470-1479 (2009)). Therefore, repeat biopsies (second, third or fourth) are necessary because of continuous elevated PSA levels (Campos-Fernandes et al. (2009), supra).
Besides PSA, other markers and methods have been identified. For example, the measurement of the level of amplification of the HER-2/neu gene by fluorescent in situ hybridization (FISH) has been disclosed to be a method of determining the severity of prostate cancer (Int'l Pat. App. Pub. No. WO 1998/045479). The determination of the presence of an amplified 8q24.1-24.2 chromosome band segment has been disclosed to be a method of diagnosing prostate cancer progression (U.S. Pat. No. 5,658,730). The determination of the loss of the 8p21-22 locus, a gain of chromosome 8, and an additional increase of the copy number of c-myc relative to the centromere copy number has been disclosed to be a method of prognosticating prostate cancer (U.S. Pat. No. 6,613,510). The determination of the hybridization pattern of a set of chromosomal probes comprising a probe to the 8p locus, such as 8p21-22, and a probe to the 8q24 locus and correlating the hybridization pattern with prostate cancer diagnosis also has been disclosed (U.S. Pat. App. Pub. No. 2003/0091994). A gain of 8q24 (c-myc) and a loss of heterozygosity of 8p21-22 (LPL) (Bova et al., Cancer Res. 53: 3869-3873 (1993); Kagan et al., Oncogene 11: 2121-2126 (1995); and Emmert-Buck et al., Cancer Res. 55: 2959-2962 (1995)) and 10q23 (PTEN) (Yoshimoto et al., Br. J. Cancer 97(5): 678-685 (Sep. 3, 2007; epub Aug. 14, 2007) also has been described. Testing for the loss of heterozygosity at one or more loci on one or more of chromosomes 1-22 has been disclosed as a method of detecting a cell with a neoplastic or preneoplastic phenotype (U.S. Pat. App. Pub. No. 2003/0165895). The detection of an increase in the level of expression of the 20P1F12/TMPRSS2 gene has been disclosed as a method of identifying prostate cancer (U.S. Pat. No. 7,037,667). The detection of a break in the sequence of human chromosome 12q24 at the SMRT gene locus using FISH has been disclosed as a method of determining the likelihood of prostate cancer metastasis (U.S. Pat. No. 7,425,414). The determination of the level of a constituent such as PTEN RNA has been disclosed as a method for evaluating the presence of prostate cancer (Int'l Pat. App. Pub. No. WO 2008/121132). The detection of an ACSL3-ETS gene fusion has been disclosed as a method of diagnosing prostate cancer (Int'l Pat. App. Pub. No. WO 2009/144460). The detection of the presence of a gene fusion having a 5′ portion from a transcriptional regulatory region of a TMPRSS2 gene and a 3′ portion from an ERG, ETV1 or ETV4 gene has been disclosed as a method of identifying prostate cancer (U.S. Pat. No. 7,718,369), as well as predicting recurrence, progression and metastatic potential (Int'l Pat. App. Pub. No. WO 2010/056993). The detection of the over-expression of PITX2 has been disclosed as a method for diagnosing the presence or risk of prostate cancer (Int'l Pat. App. Pub. No. WO 2010/099577). The identification of an increased level of a nucleic acid or polypeptide selected from OCT3/4, Nanog, Sox2, c-myc, If4, keratin 8, and uPAR has been disclosed as a method of identifying a prostate carcinoma (In't1 Pat. App. Pub. No. 2011/037643).
In addition to the above, prostate cancer “field effect” has been studied by several groups. Using digital image analysis, researchers have identified subtle changes of nuclear morphology in the histologically benign tissue adjacent to prostate cancer (Qian et al., Hum. Pathol. 28: 143-148 (1997); and Veltri et al., Clin. Cancer Res. 10: 3465-3473 (2004)). Using cDNA microarrays, the difference of gene expression profile was reported between adjacent normal tissue of prostate cancer and normal tissue obtained from organ donors (Chandran et al., BMC Cancer 5(1): 45 (2005); Yu et al., J. Clin. Oncol. 22(14): 2790-2799 (2004); and Rizzi et al., PLoS ONE 3(10): e3617 (2008)). Using immunohistochemistry, protein expression changes of multiple biomarkers were noticed in near and distant normal and high-grade prostatic intra-epithelial neoplasia (HGPIN) glands. These markers include Mcm-2 and Ki67 (Ananthanarayanan et al., BMC Cancer 6: 73 (2006); Santinelli et al., Am. J. Clin. Pathol. 128(4): 657-666 (2007)), α-methylacyl-CoA racemase (AMACR) (Santinelli et al. (2007), supra; and Ananthanarayanan et al., Prostate 63(4): 341-346 (2005)), and androgen receptor (AR) (Olapade-Olaopa et al., Clin. Cancer Res. 5(3): 569-576 (1999)), etc. Using laser capture micro-dissection and quantitative methylation-specific PCR, field effect for gene silencing through hypermethylation in prostate carcinogenesis was also found by multiple groups (Mehrothra et al., Prostate 68(2): 152-160 (2008); and Aitchison et al., Prostate 67(6): 638-644 (2007)). The genes include GSTP1, APC, RASSF1A, HIN-1 and RARb2.
In view of the foregoing, there remains a need for more reliable and informative diagnostic and prognostic methods in the management of prostate cancer. The present disclosure seeks to provide a set of markers, as well as methods of use and a kit comprising the set of markers, for the diagnosis, prognosis, and the assessment of the therapeutic or prophylactic treatment of cancer, in particular prostate cancer. This and other objects and advantages, as well as inventive features, will become apparent from the detailed description provided herein.